From CSD to headache: A long and winding road

Migraine sufferers experience pounding headaches, which sometimes are preceded by a visual aura. Now Bolay et al. show that cortical-spreading depression, the cause of the aura, activates trigeminal afferents, which act to cause inflammation of the pain-sensitive meninges, generating the headache. (pages 136–142)

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The relationship between CSD and headache in migraine with aura. CSD releases H+, K+ and other agents, including arachidonic acid (AA) and nitric oxide (NO), in the extracellular space of the neocortex.

Bob Crimi


  1. 1

    Terwindt, G.M. et al. Involvement of the CACNA1A gene containing region on 19p13 in migraine with and without aura. Neurology 56, 1028–1032 (2001).

  2. 2

    Blau, J.N. Migraine: theories of pathogenesis. Lancet 339, 1202–1207 (1992).

  3. 3

    Lauritzen, M. Pathophysiology of the migraine aura. The spreading depression theory. Brain 117, 199–210 (1994).

  4. 4

    Bolay, H. et al. Intrinsic brain activity triggers meningeal afferents in a migraine model. Nature Med. 7, 136–142 (2002).

  5. 5

    Hadjikhani, N. et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc. Natl. Acad. Sci. USA 98, 4687–4692 (2001).

  6. 6

    Bowyer, S.M., Aurora, K.S., Moran, J.E., Tepley, N. & Welch, K.M. Magnetoencephalographic fields from patients with spontaneous and induced migraine aura. Ann. Neurol. 50, 582–587 (2001).

  7. 7

    Moskowitz, M.A. & Macfarlane, R. Neurovascular and molecular mechanisms in migraine headaches. Cerebrovasc. Brain Metab. Rev 5, 159–177 (1993).

  8. 8

    Edvinsson, L. & Goadsby, P.J. Neuropeptides in the cerebral circulation: relevance to headache. Cephalalgia 15, 272–276 (1995).

  9. 9

    Kaube, H., Herzog, J., Kaufer, T., Dichgans, M. & Diener, H.C. Aura in some patients with familial hemiplegic migraine can be stopped by intranasal ketamine. Neurology 55, 139–141 (2000).

  10. 10

    Ebersberger, A., Schaible, H.G., Averbeck, B. & Richter, F. Is there a correlation between spreading depression, neurogenic inflammation, and nociception that might cause migraine headache? Ann. Neurol. 49, 7–13 (2001).

  11. 11

    Hill, R. NK1 (substance P) receptor antagonists—why are they not analgesic in humans? Trends Pharmacol. Sci. 21, 244–246 (2000).

Download references

Author information



Rights and permissions

Reprints and Permissions

About this article

Cite this article

Iadecola, C. From CSD to headache: A long and winding road. Nat Med 8, 110–112 (2002).

Download citation

Further reading